Chronic venous insufficiency is a major health problem in the United States and throughout the world. More than 7 million people are afflicted and at least 500,000 develop leg ulcerations as a consequence. An estimated 900,000 new cases arise annually. Chronic venous insufficiency is a general term that encompasses all causes of chronic venous disease. It occurs in a primary form with stretched valves and dilated venous walls, and in a secondary form following thrombophlebitis, with scarred and deformed valves and thickened venous walls with longitudinal septa and seriously compromised lumens. Other causes of venous insufficiency, such as valve aplasia, congenital malformations and external obstruction occur less often.
The clinical symptoms associated with venous insufficiency range from severe pain and recurrent ulcerations to no manifest symptoms. The site of involvement appears to be critical to the severity of the symptoms. Thus, varicosity of the superficial venous system is usually benign and the incidence of significant complications is low. In contrast, insufficiency of the deep veins or of the perforating vessels is more frequently associated with pain, swelling, ulceration, and long-term disability.
The current basic treatments for venous insufficiency rely on the prevention of reflux and a reduction of venous pressure. Conservative treatments, however, including bed rest, limb elevation, mild diuretic administration, and elastic compression stockings are aimed at the relief of symptoms rather than the underlying disease process. They are not particularly successful.
Direct valvuloplasty may be accomplished by tightening redundant cusp edges, whereas indirect valvuloplasty employs a DACRON or polytetrafluoroethylene (PTFE) cuff around the valve. Despite noticeable gains in hemodynamic measurements, clinical improvement is frequently less evident. Venous valve repair and replacement are attempts to restore competence to the deep venous system. Venous valve repair, however, suffers from the limitation that it is only suitable for those patients without prior deep venous thrombosis. In the event that the valve apparatus has been significantly degraded or destroyed, valve transplantation may be the only available option to offer symptomatic relief and a fall in venous pressure.
The quantity and quality of donor valves remain significant problems. In the typical patient as many as 30% to 40% of brachial or axillary valves are incompetent. Additionally, many patients have dilated venous systems that will not accommodate a smaller-caliber brachial or axillary vein graft. Accordingly, valve transplantation suffers from considerable constraints in its use as a surgical technique.
Small caliber vascular grafts with inner diameters of less than 6 mm are used extensively in aorta-coronary artery and infrapopliteal artery bypasses for the treatment of arterial occlusive diseases, and as arterio-venous conduits for hemodialysis access in the end stage of renal disease. At present, autogenous saphenous veins continue to be the most widely used vascular prostheses for small caliber arterial reconstructive procedures. Primary patency at four years for an arterial bypass with saphenous veins is 40–70%. A practical impediment to constructing such bypasses, however, is the fact that 10 to 40% of patients do not have an acceptable saphenous vein that can be transplanted for a successful graft.
Previous harvesting of vascular tissue for use in cardiac or vascular surgical procedures, varicose vein stripping, and prior thrombophlebitis are the most common reasons for unsuccessful autogenous saphenous vein grafting. Alternative sources of small-caliber vascular prostheses, with a patency rate comparable to or better than that of the autogenous saphenous vein, are urgently needed for clinical use.
Venous allografts from cadavers have also been used. They provide reasonable function early in the life of the graft, but yield poor results after 2 years. Modem cryopreservation techniques, including controlled-rate freezing, storage at −190° C., and cryoprotectants such as dimethyl sulfoxide and chondroitin sulfate, improve the viability of cryopreserved allograft saphenous veins. Successful results using unmodified cryopreserved allograft saphenous veins for infrainguinal tibial artery reconstructions have achieved a one-year patency rate in the range of 10 to 50%. Long-term benefits to the patient have been marred, however, by vein graft rejection and unheralded early graft closure. Complications related to the mechanical failure of the conduit itself, such as graft aneurysms or ruptures, have occurred with greater frequency and caused greater morbidity, compared to fresh autogenous veins.
Synthetic DACRON and PTFE vascular prostheses have achieved some degree of clinical success even though they are not ideal in large and mid-sized arterial reconstructions. In addition, vessel substitutes smaller than 6 mm in diameter are susceptible to early graft occlusion. The most frequently encountered failures of synthetic grafts result from thrombosis and anastomotic hyperplasia. The inherent properties of synthetic graft materials, and their limited spontaneous re-endothelialization in humans, contribute to high surface thrombogenicity.
The implantation of glutaraldehyde-fixed bovine and human umbilical vein grafts was extensively evaluated and largely discarded because of high rates of aneurysm formation occurring two years after implantation. Most of these grafts failed because of delayed vascular healing and degenerative changes. An immune response to the highly immunogenic, chemically modified venous material, was characterized by invasion of multinucleated giant cells and reduced implant recellularization. Furthermore, glutaraldehyde fixation disturbed the natural matrix protein configuration. The cytotoxic effect of glutaraldehyde inhibited cell migration into the graft wall. Degeneration in the grafts resulted in a highly thrombogenic surface and the consequent occlusion of the vessels by thrombosis.
Many factors contribute to the degree of patency achieved with a particular prosthesis. These include the inherent properties of the chosen materials, surface thrombogenicity, compliance, and porosity in the case of textile grafts. The surface properties of materials seem to be a key issue in securing the desired long-term patency of small vessel substitutes. Numerous researchers have attempted to optimize the clinical efficacy of small diameter vascular grafts by modifying the prosthetic materials to make them biologically inert, but such an inert material has yet to be developed. An alternative approach to optimize the biological components of the prosthesis-tissue complex has led to the development of biohybrid materials. Some examples include synthetic material seeded with viable cells, coatings of biological compounds such as albumin and collagen, and materials synthesized from polymers known to elicit favorable biological responses. This approach has also not yielded a practical or effective vascular prosthesis.
In general, biological materials obtained from animals or humans have unique and special microstructural, mechanical, hemodynamical, and biochemical properties that cannot be completely replicated by currently available technology. Therefore, biologically-derived materials have great potential as raw materials for implantable artificial organs. The use of porcine organs for xenotransplantation is an attractive option to overcome the shortage of available organs for transplantation into humans. However, the problem of acute rejection remains an unsolved barrier. Cell surface molecules of xenogenic organs are mainly responsible for eliciting host rejection responses. Thus, immune rejection of allogenic or xenogenic tissues and the resulting decrease in long-term durability of the graft are major obstacles to the successful development of the ideal graft.
The most immunogenic portions of allogenic or xenogenic vascular grafts are the cellular components. Mature collagen, in contrast, shows low or no antigenicity, especially when transferred from individuals of the same species. For example, induction of an immunological response against purified bovine collagen is extremely low when injected for cosmetic purposes, or in vascular grafts impregnated with bovine collagen. Chemical cross-linking of collagen, on the other hand, renders the collagen highly immunogenic and can drastically reduce its biocompatibility with the host.
A readily available, synthetic, biologic or biohybrid venous valve in various sizes would greatly facilitate valve reconstruction surgery, including the desirable goal of valve insertions in multiple sites. The development of a vascular vessel or venous valve prosthesis that avoids the long-term likelihood of thrombosis and immune rejection would revolutionize the treatment of chronic venous insufficiency.
Problems of thrombogenicity and poor tissue compatability are also encountered with implantable vascular stents. Vascular stents are supporting devices, used to strengthen or dilate a blood vessel after balloon angioplasty or endarterectomy. They are made of synthetic material that is typically thrombogenic and has poor tissue compatibility. Stents fail primarily due to thrombotic occlusion and restenosis from tissue overgrowth.
What is needed, therefore, is a graft that is durable and can maintain structural integrity. Specifically, it must retain mechanical strength in all dimensions so that dilational and elongation distortions are minimized. The graft must be capable of long-term storage. It must be available in many sizes to accommodate the wide variation of vascular reconstructions. The prosthesis must resist infection. Intraoperatively, the ideal graft should have excellent handling characteristics, including flexibility, ease of suture placement, and minimal needle-hole and interstitial bleeding. The compliance of the ideal graft should closely approximate that of the host vessel. Ideally, turbulence about the anastomoses should be minimized to decrease intimal hyperplasia. In addition, the luminal surface should be resistant to platelet aggregation and thrombosis following placement in the patient, and avoid the immunogenicity that can arise from chemical modification of biological material. Finally, in this era of cost-containment, the graft must be relatively inexpensive and easy to manufacture.